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CHAPTER 61: Principles of Antimicrobial Therapy and the Clinical Pharmacology of Antimicrobial Drugs 547

considerably more gram-negative coverage against enzyme producing and 20 mg/kg daily for amikacin are recommended. As renal func-
Enterobacteriaceae. Lastly, ceftaroline is the newest antimicrobial in tion declines, the dosing interval may also need to be extended up
the cephalosporin class and is considered an anti-MRSA cephalospo- to every 48 hours. Due to the narrow therapeutic index of amino-
rin. Ceftaroline is the only cephalosporin with activity against MRSA, glycosides therapeutic drug monitoring is necessary for efficacy and
including strains such as vancomycin intermediate S aureus (VISA) safety. The use of a nomogram, such as the Hartford Hospital Once
and heteroresistant VISA. Its gram-negative activity is similar to that Daily Aminoglycoside nomogram, is often utilized in institutions to
of ceftriaxone and it does not have activity against P aeruginosa. The help guide clinicians to ensure appropriate use of these agents. This
most commonly used cephalosporins in the ICU are ceftazidime and nomogram was evaluated in approximately 2000 patients at Hartford
cefepime due to their broad spectrum of gram-negative activity, which Hospital and found to reduce nephrotoxicity when administered once
is inclusive of P aeruginosa. Both ceftazidime and cefepime are dosed daily. Importantly, using a 7-mg/kg dose achieved average serum
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aggressively because patients are likely to have altered pharmacokinet- peaks of 20 µg/mL, which was 10 times the MIC of P aeruginosa
90
ics, which puts them at risk for inadequate drug exposure. Both agents (2 µg/mL) at the institution. Depending on the institution’s aminogly-
are typically dosed at 2 g every 8 hours for patients with normal renal coside MICs, doses may need to be altered to meet the same C max : MIC
function. While they can be administered as intermittent infusions, target ratio. Understanding an institution’s susceptibility patterns is
similar to other β-lactams, there is substantial benefit in administering paramount in treating patients effectively. The ultimate goal in thera-
these agents as extended infusions. peutic drug monitoring is to minimize toxicity and maximize efficacy.
Similar to penicillins and carbapenems, f T > MIC is considered An aminoglycoside level should be drawn 6 to 14 hours after infusion
the predictive pharmacodynamic parameter for cephalosporins. Most of the first dose. Due to all the changes in critically ill patients, levels
studies have associated an f T > MIC of 50% to 70% with successful may need to be drawn relatively frequently depending on the clinical
clinical outcomes for gram-negative infections. 29,30 Prolonged infusions stability of the patient.
of cephalosporins, particularly with ceftazidime and cefepime, have been While aminoglycoside monotherapy may be effective against
shown to produce beneficial clinical outcomes. Three-hour infusions of organisms with lower MICs, organisms with higher MICs are much
cefepime 2 g every 8 hours in the VAP clinical pathway mentioned above more difficult to treat and critically ill patients often have pathogens
reduced infection-related mortality and infection-related length of stay. with higher MICs. Therefore, it is often recommended that amino-
Most notably, some of these patients achieved successful outcomes glycosides should be used in combinations with β-lactams or even
despite being infected with P aeruginosa isolates with MICs at or above fluoroquinolones.
Typically these agents are administered intravenously; however,
the breakpoint. aerosolized administration of aminoglycosides has been used for
■ AMINOGLYCOSIDES some patients with pneumonia. Avoiding intravenous administration
helps prevent nephrotoxicity and has also been proven to improve the
Aminoglycosides have been used for many years to treat serious clinical outcomes of these patients. One study in patients infected with
gram-negative infections. Amikacin, gentamicin, and tobramycin are P aeruginosa showed that patients treated with aerosolized aminogly-
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currently the three most commonly used aminoglycosides. Generally cosides had a higher microbiological cure rate and were more likely
speaking, aminoglycosides have activity against gram- negative bacilli to have resolution of clinical symptoms when compared with patients
and staphylococci, however there are a few differences between the treated intravenously.
three agents. The potency of tobramycin makes it a better agent for
Pseudomonas while gentamicin is more potent against Enterobacteriaceae ■
and staphylococci species. POLYMYXINS
Appropriate dosing of this class of antimicrobials is essential for The polymyxin class of antimicrobials includes polymyxin B and E.
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safety and efficacy. Aminoglycosides display concentration-dependent However, polymyxin E, also known as colistin, is the most widely used
killing and therefore the pharmacodynamic driver for efficacy is of the two. Colistin was first introduced in the 1960s, however due to
C max : MIC ratio. Specifically, a C max : MIC ratio of ≥10 has been related the significant neurotoxicity and nephrotoxicity associated with the
to clinical success. The volume of distribution of this class of anti- agent it was rarely used. Unfortunately, due to the rise of multidrug-
5
microbials is often lower in patients with critically ill conditions such resistant organisms, the use of colistin has increased as antimicrobial
as sepsis and severe burns, which can subsequently lead to decreased options for these difficult to treat pathogens remain limited. Colistin
serum peaks. Additionally, depending on the MIC of the organ- is administered as colistin methanesulfonate (CMS), an inactive pro-
1,32
ism, the C max : MIC ratio can change significantly. The elimination drug, which undergoes conversion to colistin in vivo. Colistin has a
half-life in patients with normal renal function is approximately 2 to relatively narrow antimicrobial spectrum of activity and is most com-
3 hours, however this can be significantly altered in patients with acute monly used to treat serious infections caused by resistant gram-negative
kidney injury or poor renal function. Therefore, the patient’s renal pathogens including P aeruginosa, Acinetobacter spp, and Klebsiella
31
function can greatly affect the pharmacokinetic exposure. Since these spp. Although it has been available for many years, pharmacokinetic
agents are eliminated largely unchanged via the kidney, nephrotoxic- information about colistin is relatively sparse. Recent studies including
ity is a significant concern. The risk of nephrotoxicity is relatively the pharmacodynamic in vitro models and neutropenic mouse thigh and
same among the different aminoglycosides. Concomitant vancomycin lung infection models have shown that fAUC : MIC of 12 to 15 best
therapy, increased age, prolonged duration of therapy, and preexist- correlates with efficacy. Recommended dosing is 2.5 to 5 mg/kg per day
ing renal or liver disease increase the risk of aminoglycoside neph- in two to four divided doses, however recent pharmacokinetic stud-
rotoxicity. Ototoxicity is another adverse effect of aminoglycoside ies have shown that these doses may provide suboptimal exposures in
therapy as these agents penetrate into cochlear tissues. Risk factors critically ill patients. 35-37 Additionally, the clearance of CMS and colistin
include prolonged therapy, prior treatment with aminoglycosides, and is largely dependent on renal function and will have a direct impact

preexisting renal disease. on antimicrobial exposure. The impact of low colistin concentrations
Traditionally, aminoglycosides were dosed two to three times a day. is relatively substantial as it has been associated with an amplification
However, this often results in peak concentrations below the phar- of colistin-resistant subpopulations. The administration of a loading
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macodynamic threshold and is also associated with higher nephro- dose has been suggested so that colistin exposure during the initial
and ototoxicity. Alternatively, once daily dosing provides higher 12 hours of therapy is large enough to provide more net killing and pre-
peak concentrations and a lower risk of toxicities. For patients with vent the resistant subpopulation. Optimal dosing of this agent has yet to be
normal renal function 7 mg/kg daily for gentamicin and tobramycin determined and continues to pose a significant challenge due to toxicity.

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